The present invention relates to a method for the treatment of autoimmune diseases, which are effectively treated by administering the compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is thought to be mediated by an autoimmune attack directed against CNS myelin antigens. Based on animal models, as well as on data gathered from analyses of leukocytes and tissues from patients with MS, antigen specificity is considered to reside within T cells expressing the xcex1xcex2 T cell receptor (TCR), with encephalitogenic activity dependent on the expression of a cytokine profile characteristic of a Th1-type phenotype: interferon-gamma (IFNxcex3), lymphotoxin (LT) and tumor necrosis factor-alpha (TNFxcex1). T cells that express a Th2-type cytokine profile (IL-4, IL-5 and IL-13) or regulatory cytokines such as transforming growth factor-beta (TGFxcex2) and IL-10, are thought to interfere with this process by blocking the acquisition of the Th1-phenotype and/or by blocking the downstream targets of effector cytokines, such as the activation of macrophages.
The critical nature of the cytokine profile of the antigen-reactive xcex1xcex2 T cells to disease expression raises the question as to the nature of the antigen recognition process that results in the acquisition of these specific cytokine profiles. Although it has been known for some time that the presence of adjuvants and the route of antigen presentation are important determinants of encephalitogenic activity in animals, how these processes shape the nature of the acquired immune response, as well as the contribution of other non-antigen-specific leukocyte populations, have only recently started to come into sharper focus with an expanding recognition of the different cell populations that function at the interface between the innate and acquired immune response.
The innate immune response functions as a first line of defense against a wide range of infectious and toxic agents. Historically, this response has been attributed to cells with phagocytic activity, such as macrophages and polymorphonuclear cells, and/or potent cytotoxic activity, such as natural killer cells (NK cells), mast cells and eosinophils. The activity of these different cell populations is aided and abetted by a number of different soluble molecules collectively known as acute phase proteins, such as the interferons, specific components of the complement cascade and cytokines, that serve to enhance phagocytic and cytotoxic activity, as well as lead to the accumulation of these cells at sites of tissue injury. If these first lines of defense are breached, then activation of the adaptive immune response ensues, leading to the formation of a specific immune response that may display anyone of a number of different characteristics. The generation of this acquired immune response is an exclusive property of lymphocytes.
More recently, however, it has become recognized that minor subpopulations of lymphocytes may also function as part of the innate immune response. Although it is likely that the complete functional role of these specialized subsets of lymphocytes remains poorly understood, current interest in them has focused on their role in defining the cytokine milieu at sites of tissue injury, influencing the nature of the adaptive immune response that is generated. Thus, many of these studies have focused on the role of IFNxcex3 and IL-12 in defining a Th1-type cytokine profile and IL-4 a Th2-type cytokine profile. Subpopulations of all of the three major groups of lymphocytes, xcex1xcex2 T cells, xcex3xcex4 T cells and B cells, likely fall into this category. These lymphocyte populations are characterized by the use of a highly conserved antigen receptor complexes, expression of additional pattern-recognition receptors, such as members of the Toll-like receptor family or receptors normally detected on NK cells, and the rapid release of high levels of cytokines and chemokines following interaction with specific ligands.
xcex3xcex4 T cells: T cells expressing the xcex3xcex4 T cell receptor (TCR) constitute a minor population of the total circulating T cell population. In common with xcex1xcex2 T cells, xcex3xcex4 T cells express a rearranged TCR, but the mechanisms involved in the acquisition of TCR diversity, as well as the nature of the antigens recognized, are clearly different (Chien Y. H. et al. Annu. Rev. Immuniol. 1996;14:511-32). Analysis of CDR3 length distributions, as well as crystallographic studies, have suggested greater structural similarity of the xcex3xcex4 TCR to immunoglobulin heavy chain genes, lending further support to the conclusion that the molecular nature of antigen recognition by xcex3xcex4 T cells is fundamentally different from that utilized by xcex1xcex2 T cells. xcex3xcex4 T cells also differ from xcex1xcex2 T cells in that most xcex3xcex4 T cells coexpress receptors found on natural killer cells (NKxe2x80x94R) (Battistini L. et al.; J. Immunol. 1997;159:3723-30). Expression of these receptors on T cells has been shown to modulate several T cell functions including cytotoxicity, cytokine release and transendothelial cell migration (Reyburn H. et al., Immunol. Rev. 1997;155:119-25) These data indicate that the regulation of xcex3xcex4 T cell function is likely to be different from that found in most xcex1xcex2 T cells, involving activation (or inhibition) by signaling through both the TCR and NKxe2x80x94R. It has been suggested that NKxe2x80x94R functions as costimulatory molecules that are exquisitely responsive to changes in cell surface expression of MHC modulated by infection or to the activation state of the cells (Reyburn H. et al., ibid.).
In healthy adults the majority of xcex3xcex4 T cells express a TCR that utilizes the Vxcex39Vxcex42 gene segments The expansion of this specific population of xcex3xcex4 T cells is thought to be due to a response to non-protein bacterial antigens such as pyrenil-pyrophosphate derivatives and other components of bacterial cell walls, without classical MHC-restriction (Salerno A et al., Crit. Rev. Immunol. 1998;18:327-57)). The response to these types of antigens has been found to be critically dependent upon the use of germline encoded lysine residues in the Jxcex31.2 segment (Miyagawa F. et al., J. Immunol. 2001;167:6773-6779). Thus, although the response to phosphate antigens may be polyclonal in nature, conserved elements are used by the responding cells. Conserved sequences of xcex3xcex4 T cell receptor have been noted in cells and/or tissues isolated from patients with MS, suggesting a response to a common antigen.
xcex3xcex4 T cells share many features in common with the xcex1xcex2TCR+NK-T cells, including the expression of NK receptors, constitutive expression of the IL-2rxcex2, usage of highly conserved TCR sequences and restriction, at least for some subsets, by CD1 molecules (Spada F. M. et al, J. Exp. ed. 2000;191:937-48). This would suggest that some xcex3xcex4 T cells may provide a similar link between the innate and acquired immune response (Poccia F. et al., Immunol. Today 1998;19:253-6). Consistent with such a notion is that activation of Vxcex42+ T cells with phosphate antigens has been shown to lead to the rapid release of large amounts of both cytokines and chemokines (Poccia F. et al., J. Immunol. 1997;159:6009-17; Cipriani B. et al, Blood 2000;95:39-47). Interestingly, there are accumulating data that suggest that V region usage may implicate specific subsets of xcex3xcex4 T cells in mediating Th1 or Th2-type responsesxe2x80x94with Vxcex42+ cells showing a Th1-type bias and Vxcex41+ cells a Th2-type bias. So for example, it has been shown that xcex3xcex4 T cells in MS lesions express a predominantly Vxcex42 phenotype (Battistini L. et al., Mol. Med. 1995;1:554-62) and that Vxcex42 cells in the peripheral blood of patients with MS show evidence of activation. In the CSF, however, Vxcex41 cells are the predominant xcex3xcex4 T cell population (De Libero G., Springer Semin. Immunopathol. 2000;22:219-38)
Studies that have examined a potential role for xcex3xcex4 T cells in demyelinating diseases further support the conclusion that although xcex3xcex4 T cells show evidence of activation in patients with either MS or Gulllain Barrxc3xa8 syndrome (GBS), differences exist in the phenotypic and functional properties of these cells in the two diseases In particular, the data indicate that in patients with MS the Vxcex42 subset is activated and that these cells can be induced to secrete high levels of proinflammatory cytokines.
Once activated via the TCR, xcex3xcex4 T cells may also function as NK cells, responding in either a positive or negative fashion to NK cell targets (Battistini L. et al., J. Immunol. 1997;159:3723-30; De Libero G. Microbes Infect. 1999;1:263-7) Furthermore, in MS patients with active disease, the percentage of circulating Vxcex42+ T cells coexpressing NKRP1A (the human homologue of NK1.1) has been found to be significantly increased compared with healthy donors. When Vxcex42+ and Vxcex41+ T cells were sorted from MS patients and healthy volunteers and cloned, all Vxcex42+ clones expressed NKRP1A. NKRP1A was strongly up-regulated on Vxcex42+ cells by culture with IL-12 whereas no up-regulation of NKRP1A by IL-12 was noted on Vxcex41+ clones. In transendothelial migration assays, Vxcex42+ NKRP1A+ clones migrated more effectively than Vxcex41+ clones, and this migratory potential was enhanced following culture with IL-12. Migration was strongly inhibited by the F(abxe2x80x2)2 of an anti-NKRP1A antibody, suggesting that this receptor for common lectins is involved in the transendothelial cell migration process. It was also shown that in freshly isolated PBMC from MS patients, the migrated population was enriched in Vxcex42+ NKRP1A+ cells. Thus the expression of NKRP1A on Vxcex42+ cells is associated with an increased ability to migrate across the vascular endothelium, an activity that may be upregulated by IL-12 present in the microenvironment (Poggi A. et al., J. Immunol. 1999;162:4349-54). Taken together, these data suggest that xcex3xcex4 T cells could be rapidly recruited to sites of inflammation in the CNS where they could significantly contribute to the cytokine/chemokine balance of the lesion, as has been demonstrated in EAE (Spahn T. W. et al, Eur. J. Immunol. 1999;29:4060-71, Rajan A. J. et al., J. Immunol. 2000;164:2120-30).
Accordingly the availability of a compound having immunomodulatory properties on the innate immune response of effector xcex3xcex4+ T cells would be of great benefit to the subjects in need thereof.